title: Determinants of mercaptopurine toxicity in paediatric acute lymphoblastic leukemia maintenance therapy.
abstract: OBJECTIVE
  6-mercaptopurine (6-MP) is used in the treatment of childhood acute lymphoblastic leukaemia (ALL). Its red blood cell (RBC) metabolite concentrations (6-thioguanine [6-TGN] and 6-methylmercaptopurine nucleotides [6-MMPN]) are related to drug response. We investigated the impact of non-genetic covariates and pharmacogenetic polymorphisms affecting thiopurine methyltransferase (TPMT) and inosine triphosphate pyrophosphatase (ITPA) on 6-MP metabolism and response.
  
  
  METHODS
  Sixty-six children with ALL treated according to EORTC 58951 protocol were included in this study. Six patients had a heterozygous genotype for the most common TPMT polymorphisms, nine for ITPA 94 C > A and 17 for ITPA IVS2+21 A > C. 6-MP metabolites concentrations were analyzed by mixed model analysis.
  
  
  RESULTS
  During maintenance, steady-state RBC 6-TGN concentrations were lower in patients aged 6 years or younger (493 pmol/8 × 10(8) RBC) than in older children (600 pmol/8 × 10(8) RBC). 6-MMPN concentrations were low in patients with TPMT variant/wild-type ITPA (1862 pmol/8 × 10(8) RBC), intermediate in wild-type patients and high (16468 pmol/8 × 10(8) RBC) in patients wild-type TPMT/variant ITPA. A 6-MMPN threshold of 5000 pmol/8 × 10(8) RBC was associated with an increased risk of hepatotoxicity.
  
  
  CONCLUSIONS
  In this study, age and both TPMT and ITPA genotypes influenced 6-MP metabolism. High 6-MMPN was associated with hepatotoxicity. These pharmacological tools should be used to monitor ALL treatment in children.
authors.affiliation: Department of Pediatric Pharmacology and Pharmacogenetics, Robert Debre Hospital, Paris, France.
authors.forename: Tiphaine
authors.initials: T
authors.lastname: Adam de Beaumais
authors.forename: May
authors.initials: M
authors.lastname: Fakhoury
authors.forename: Yves
authors.initials: Y
authors.lastname: Medard
authors.forename: Said
authors.initials: S
authors.lastname: Azougagh
authors.forename: Daolun
authors.initials: D
authors.lastname: Zhang
authors.forename: Karima
authors.initials: K
authors.lastname: Yakouben
authors.forename: Evelyne
authors.initials: E
authors.lastname: Jacqz-Aigrain
mesh_terms: D000367:Age Factors; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects* / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology*; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000187:drug effects; D005838:Genotype; D006801:Humans; D008099:Liver / Q000187:drug effects*; D015122:Mercaptopurine / Q000009:adverse effects* / Q000378:metabolism; D011110:Polymorphism, Genetic; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics; D013223:Statistics as Topic; D013866:Thioguanine
chemical_list: D000964:Antimetabolites, Antineoplastic; D015122:Mercaptopurine; D013866:Thioguanine